Post-transcriptional regulation of expression of the potassium channel, Kv1.1

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Post-transcriptional regulation of expression of the potassium channel, Kv1.1

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Title: Post-transcriptional regulation of expression of the potassium channel, Kv1.1
Author: Allen, Margaret Louise
Abstract: Potassium channels (K channels) are important in setting resting membrane potentials, shaping action potentials, modulation of hormone and neurotransmitter release and regulation of neuronal firing patterns (Hille, 1992; Jan and Jan, 1997). K channels are pivotal to many physiological functions and in fact a number of human diseases have been shown to be caused by K channel mutations (Biervert et al., 1998; Browne et al., Charlier et al., 1998; 1994; Singh et al., 1998; Zerr et al., 1998). Since K channels are critical to normal physiology, it is important to understand regulation of expression of these genes. We report here identification of the transcriptional start sites and basal proximal promoter region for the mouse K channel, mKv1.1. Sequencing analysis reveals high sequence conservation of the proximal promoter and 5$\sp\prime$UTR regions of the mouse and human Kv1.1 genes. There is an intronic sequence in the 5$\sp\prime$UTR of Kv1.1 that is present in 50% of cDNA clones (Tempel et al., 1988). We demonstrate that this intron is spliced out of mature, translated Kv1.1 RNA. In addition to the transcriptional elements, we demonstrate that the endogenously expressed Kv1.1 transcript in the C6 glioma cell line is rapidly destabilized with elevation of intracellular cAMP without a significant change in the transcription rate. This cAMP induced decrease in the steady state Kv1.1 RNA level is followed by a decrease in Kv1.1 protein and a decrease in a delayed-rectifier type K$\sp+$ current measured by whole-cell patch clamp electrophysiology. We demonstrate that Kv1.1 is important in maintaining the resting membrane potential in C6 glioma. Finally, we demonstrate that proliferation of C6 glioma is inhibited by conditions which destabilize the Kv1.1 transcript. This level of inhibition of proliferation is the same as that obtained when C6 glioma are cultured in the presence of the K channel blockers, 4AP and TEA. In conclusion, we have demonstrated that regulation of expression of the K channel, Kv1.1, occurs at the level of transcript stability and is correlated with elevation of intracellular cAMP concentrations. We speculate that this mechanism of regulation allows for rapid and dynamic control of expression of Kv1.1.
Description: Thesis (Ph. D.)--University of Washington, 1998

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